Brentuximab Vedotin (3) – Adcetris®

• Clinical trials
  • For the benefit assessment of the active ingredient brentuximab vedotin, the pharmaceutical manufacturer submitted the pivotal, open-label, randomised, multicentre Phase III trial C25001 (ALCANZA).
  • As supporting evidence, the pharmaceutical manufacturer cited the two open-label, single-arm, monocentric Phase II trials 35-IST-001 and 35-IST-002.

a) adult patients with CD30+ cutaneous T-cell lymphoma (CTCL) who have received at least one prior systemic treatment

• mortality
  • overall survival
  • Overall survival was assessed as a safety endpoint in the ALCANZA study and analysed post hoc.
  • The median survival time had not been reached in any study arm at the time of the final data cut-off.
  • Overall, there was no statistically significant difference between the treatment arms.
  • An additional benefit of brentuximab vedotin over the control treatment with methotrexate or bexarotene is not proven for overall survival.
• morbidity
  • Progression-free survival (PFS), objective response rate ≥ 4 months (ORR4)
  • For the PFS endpoint, there is a statistically significant advantage of treatment with brentuximab vedotin compared with control therapy.
  • The median time to progression was 16.7 months for patients in the brentuximab vedotin arm and 3.5 months in the control arm (HR 0.27; 95% CI [0.17; 0.43]; p < 0.001; absolute difference: 13.2 months).
  • The ORR4 was assessed by the IRF on the basis of the Global Response Score (GRS).
  • For the ORR4 endpoint, there was a statistically significant advantage for treatment with brentuximab vedotin (risk difference 43.8%; 95% CI [29.1; 58.4]; p < 0.001).
  • The endpoints PFS and ORR4 are composite endpoints; in the case of PFS, they comprise endpoints from the mortality and morbidity categories, and in the case of ORR4, they comprise endpoints from the morbidity category.
  • The assessment of the morbidity components ‘disease progression’ and ‘response of lymph nodes, internal organs and blood’ was carried out in the areas of lymph nodes, internal organs and blood in accordance with the operationalisation; this was not symptom-based, but rather based on imaging procedures and laboratory parameters.
  • Consequently, the assessment of response in these areas is based on asymptomatic findings and is therefore considered not to be directly relevant to the patient.
  • Skin lesions were assessed using the mSWAT.
  • Nevertheless, there is a lack of information regarding the (evidence-based) basis for the weighting factors used for the type of skin lesion (patches, plaques, tumours) and the rationale for incorporating skin lesions with different prognoses into a combined score.
  • Furthermore, no data on inter-rater reliability are available.
  • The validation study cited by the pharmaceutical manufacturer shows no significant correlation between the mSWAT and the Skindex-29.
  • There is therefore doubt as to whether the mSWAT, the measurement tool used to assess skin response, is sufficiently valid and reliable to reflect the cutaneous burden of disease.
  • Taking into account the comments from the professional societies and the burden on the patient, the changes in the skin measured using the mSWAT in this rare indication are presented in this assessment.
  • Cutaneous symptoms – symptom domain of the Skindex-29
  • Analyses are available on the maximum change in cutaneous symptoms between baseline and during the treatment phase (including the end of treatment).
  • These show statistically significant differences between the study arms in favour of brentuximab vedotin, both for the maximum improvement (maximum reduction) and for the maximum worsening (maximum increase).
  • The statistically significant maximum improvement in cutaneous symptoms with brentuximab vedotin is clinically relevant according to Hedges’ g (-0.85; 95% CI [-1.23; -0.46]).
  • With regard to the presented results on the maximum improvement and maximum worsening of cutaneous symptoms, it should be noted that the treatment durations differ significantly between the two study arms.
  • The assessment of cutaneous symptoms for patients in the brentuximab vedotin arm was therefore carried out significantly more frequently than in the control arm.
  • For this reason, there is a bias in favour of brentuximab vedotin for the maximum improvement and a bias against it for the maximum worsening.
  • The results must therefore be regarded as highly biased.
  • Cutaneous symptoms – maximum improvement and maximum worsening of the unweighted proportions of skin lesions relative to the total body surface area
  • With regard to the maximum improvement in cutaneous symptoms, brentuximab vedotin showed a statistically significant and, according to Hedges’ g, clinically relevant advantage over the control arm for tumours (0.59; 95% CI [0.23; 0.96]).
  • With regard to maximum deterioration, treatment with brentuximab vedotin also showed statistically significant advantages for tumours and plaques.
  • Clinical relevance according to Hedges’ g is evident only for tumours (0.59; 95% CI [-0.96; -0.22]).
  • Due to the varying durations of treatment, there is a bias in favour of brentuximab vedotin for maximum improvement and a bias against it for maximum deterioration.
  • Cutaneous symptoms – Maximum reduction and maximum increase in the mSWAT score
  • Between the study arms, a difference is observed both in the maximum reduction (mean difference: 11.77%; 95% CI [3.02; 20.53]; p < 0.01) and in the maximum deterioration (mean difference: –11.92%; 95% CI [–20.83; –3.01]; p < 0.01) in the mSWAT score.
  • According to Hedges’ g, the differences in the mSWAT score are not considered clinically relevant.
  • Cutaneous symptoms – complete remission
  • Complete remission of skin symptoms occurred in 26.6% of patients in the brentuximab vedotin arm and in 1.6% of patients in the control arm in the overall population.
  • Complete resolution of all cutaneous symptoms was thus statistically significantly more common with brentuximab vedotin than in the control arm (relative risk: 17; 95% CI [2.33; 124]; p < 0.001).
  • In the brentuximab vedotin arm, both patients with MF (16.7%) and those with pcALCL (56.3%) achieved complete skin remission more frequently than in the control arm (0% and 6.7%, respectively).
  • In summary, treatment with brentuximab vedotin results in a clear advantage over the control arm in terms of complete skin remission.
  • health status
  • There is no statistically significant difference in the mean differences in changes between baseline and the end of treatment across the treatment arms.
  • Hospitalisation
  • There was no statistically significant difference between the treatment arms in the number of patients who were hospitalised.

Courtesy translation only, please refer to the German original.